Dihydropyridine derivatives belong to the pharmacological class known as calcium antagonists. They are indicated in a plurality of heart/circulatory diseases, for example, coronary heart disease, arterial hypertension, angina pectoris and so on. The prescription of over 700 million defined daily doses in the year 1989 clearly shows the market position of this class of substances. The first member of this group is Nifedipin (1,4-dihydro-2,6,-dimethyl-4-(2-nitrophenyl)-3,5-pyridine carbonic acid dimethylester, C.sub.17 H.sub.18 N.sub.2 O.sub.6) has already given rise to a plurality of potent derivatives, the so-called second generation dihydropyridines, Nitrendipin 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine carbonic acid ethyl-methyl ester, C.sub.18 H.sub.20 N.sub.2 O.sub.6 and Nisoldipin isobutyl-methyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dic arboxylate, C.sub.20 H.sub.24 N.sub.2 O.sub.6.
The dosage form of the conventional nifedipin acute dosage form for single doses is, generally speaking, 5 to 10 mg. while the newer dihydropyridine derivatives are at this time, dosed at lower level.
Many galenic developments have been suggested in order to bring dihydropyridine, in particular nifedipin, into the organism at a sufficient speed, by rapidly releasing the active substance from the dosage form. These, however, take into a account a plurality of compromises because on the one hand, the difficult solubility or insolubility of these active substances in a physiological environment provides barriers to or makes more difficult their release from the dosage form. On the other hand, a rapid release is the criterion for the fastest entry into action after dosing. These requirements are not inconsiderable for raising the level of patient compliance.
At the present time the technological methods utilized for the production of dosage forms of dihydropyridine derivatives, in particular nifedipin are as follows:
a) Processing of the active substance with solvating agents (tensides) and additionally PA1 b) Dissolving the active substances in organic solvents, for example polyether alcohols of tetrahydrofurfuryl alcohols. PA1 a) a skeleton former selected from the group consisting of gelatin, fractionated gelatin, collagen hydrolysate and gelatin derivatives as well as mixtures thereof are dissolved in a solvent. PA1 b) the dihydropyridine derivative is dispersed in the smallest possible particles in the solution, PA1 c) the dispersion of the skeleton former and the dihydropyridine derivative are dropped into an exceedingly cold inert solvent to form the pellets, and PA1 d) the pellets are dried. PA1 Title: "Aloe Vera Juice Containing Pellets for Production Thereof and the Use Thereof as Pharmaceutical Cosmetic and Peroral Agents", U.S. Ser. No. 07/876,876. PA1 Title: "Pellets Containing Peptides, Method of Making Same and Use Thereof", U.S. Ser. No. 07/876,865. PA1 Title: "Means for Containing Active Substances Having a Shell of Hydrophilic Macromolecules, Active Substances and Process for Preparation Thereof", U.S. Ser. No. 07/876,864. PA1 Title: "Peroral Dosage Form for Peptide Containing Medicaments, in Particular Insulin", U.S. Ser. No. 07/876,867.
Because of the light sensitivity of dihydropyridine a conventional, colored soft gelatin capsule may be utilized, for example, as carrier (light protection) for the above mentioned nifedipin solubilisate or nifedipin solution in an organic solvent. After dosing, the nifedipin should be released from the dosage form in finely divided form. Herein however, it must be considered that the active substance is thereafter not really in a free form but must first be released from its complex with the solvating agent which has the disadvantage that it is not sufficiently rapidly available for the organism.
Furthermore, this mode of proceeding also has the possible risk that under physiological conditions, the nifedipin is precipitated in a crude crystalline form as soon as the solvating agent (tenside) is no longer active. Furthermore, the use of tensides or organic solvents is not without problems with respect to toxicological considerations.
Liquid nifedipin preparations which can be utilized in drop form are equally commercially available. Patients particularly like the dosage form of these nifedipin drops, in particular, elderly patients who have found the swallowing of solid formulations (tablets, capsules) to be unpleasant or have difficulties therewith. Furthermore, they have the advantage of accurate dosing.
While the liquid dosage forms (from a technological point of view) are a well conceived dosage form, (the process of the disassociation of solid, "single unit" forms as well as, for example, tablets or capsules is irrelevant), these preparations, with respect to the dihydropyridines are not opportune. In addition to the reasons set forth above (presence of tensides and/or organic solvents), there is further more extensive reason to seek this class of compounds. It is known that dihydropyridines are exceedingly light sensitive and tend to dissociate, in particular in solutions. Thus, particularly during the extraction of the nifedipin drops by the patient from the storage container, one cannot exclude the possibility of a partial dissociation of the nifedipin by the action of light even before administration. Since this dosing, particularly with older patients, is a rather time-consuming process, the risk of dissociation of the active substance before actual intake is considerably increased.
Further, it should be noted that even the storage of solutions of nifedipin for drops, in brown or dark colored glass bottles does not yield sufficient extended storage stability (protection from the action of light). On pharmacological grounds alone, it would be desirable, in fact advantageous, to provide a preparation of dihydropyridine derivations in a rapidly available acute dosage form which as a solution of the active substance. However, because of the physicochemical properties of the active substance as for example insufficient water solubility, light sensitivity in solution and so on, such a goal is either unreachable or only via considerable detours.
The task of the present invention therefore is to provide a dosage form for oral or peroral administration of dihydropyridine derivatives, in particular nifedipin which provides for rapid release of the active substance and overcomes the problems of the state of the art.